This is a competitive renewal application of a project to identify susceptibility loci for infantile autism. Autism is a severe neurodevelopmental disorder with onset usually in the first three years of life. It is characterized by marked social deficits, delay in language development, and a restricted range of stereotyped repetitive behaviors. The prevalence of autism is about 1 in 2,500 births, and the ratio of affected boys to girls is around 3:1. Although the exact causes of autism are unknown in most cases, family and twin studies strongly support a genetic etiology. Although the family studies strongly support a genetic etiology the very high ratio of MZ to DZ (or sib) concordance is very indicative of multiple Loci with interactive effects. However, given the very high overall ratio of sib recurrence to population prevalence (approximately 75-fold), there is considerable power to detect susceptibility loci even if there are many of them. Thus, we are employing an affected sib pair strategy and an entire genome screen to search for as many contributing susceptibility loci as can be identified. In the process, we will produce an exclusion map to define all regions that contain no such loci. In the initial phase of this project we have already collected and immortalized cell lines from 80 affected sib-pair families including parents. We now propose to complete the family recruitment/assessment to obtain a total of 200 families with at least two affected sibs, including immortalization of cell lines. We intend to genotype 100 of these families with 330 highly polymorphic markers (PIC = 0.70) spaced 10 cm apart covering the entire genome and construct an exclusion map using multipoint sib-pair analysis. Regions not excluded will be saturated with additional polymorphic markers and genotyped these 100 and the second set of 100 families. Thus, we will exclude previously unexcluded regions, as well as identify a region or regions likely to contain a susceptibility locus or loci. For the latter, will define 95% confidence regions to contain a susceptibility locus. In these regions, using markers spaced approximately 1 Cm apart, we will search for linkage disequilibrium to further localize any susceptibility loci, and set the stage for positionally cloning these genes. Autism is a devastating neuro-psychiatric disorder that creates suffering for those affected as well as their family members. By identifying susceptibility genes, we hope to eventually understand the pathophysiological pathways underlying this disease, leading to effective prevention and/or treatments.